Process for the preparation of 17alpha-acyloxy-6-methyl-16-methylene-4, 6-pregnadiene-3, 20-diones and intermediates obtained therefrom



United States Patent Office Patented July 25, 1967 This application is adivision of our copending application Ser. No. 41,256, filed July 7,1960.

This invention is for improvements in or relating to organic compoundsand has particular reference to new steroidal acyloxydiene diones havingthe general Formula I below and a method for their preparation.

It is an object of the invention to provide new acyloxydienedioneshaving the general Formula I below which compounds are of value onaccount of their biological properties and in particular on account oftheir progestational properties. Thus it is an object of the presentinvention to provide the acetoXy derivative (I; R=Ac) which is anexceptionally active progestational agent. For example, in the Claubergassay it has a progestational activity when administered orally of 100times that of dimethisterone (6a:21-dimethylethisterone, which has aprogestational activity of times that of pregneno1one-17otethinyl-A-androstan-1718-01-3-one. The acetoxy derivative (I; R=Ac) is also anexceptionally active ovulation inhibitor. Additionally, it is inactiveas an oestrogen and has no anabolic or androgenic activity. Itspotential progestational activity renders the material of great value inmedical and veterinary practice whether as tablets, elixirs,suppositories or injections.

The invention also provides the new intermediates According to thepresent invention there is provided a process for the preparation of17a-acyloxy-6-methyl-16 methylenepregna-4,6-diene-3,20-diones having thegeneral formula (where R is an acyl group containing up to 6 carbonatoms) which process comprises oxidising a 3fl-hydroxy or3B-acyloXy-6,l6-dimethylpregna-5,16-dien-20 one having the generalformula Me (II) (where R is hydrogen or an acyl group containing up to 6carbon atoms) to the corresponding 16a,l7a-epoxide having the generalformula (III) (where R is hydrogen or an acyl group containing up to 6carbon atoms), acylating the 16a,17 x-epoxide in cases where R'=H,converting the 16a,17a-epoxide into a 17a-hydroxy-16-methylenederivative having the general formula (where R is an acyl groupcontaining up to 6 carbon atoms) by treatment with a source of hydrogenions, subjecting the 17a-hydroXy-16-methylene derivative to enforcedacylation to give a diacyl derivative having the formula O OMe carbonatoms) and subjecting the 3fi-hydroxy-l7aacyloxy derivative to anOppenauer oxidation.

The preparation of the 3,8-hydroxy or 3fi-aeyloxy-6,16-dimethylpregna-5,16-dien--one (II) employed as starting material in thepresent invention is described in our copending application No. 824,961,now Pat. No. 3,028,- 381.

It is unequivocally established by prior art that16a,17aepoxypregnan-ZO-ones on treatment with hydrogen halides, followedby catalytic reduction of the halohydrin thus produced, yield thecorresponding 17a-hydroxypregnan-ZO-ones but we have found that reactionof the 16- methyl-l6a,17a-epoxypregnan-20-one with a source of hydrogenions, such as a hydrogen halide, gives a product which we formulate asthe corresponding 16-methylenel7a-hydroxypregnan-20-one because itsinfra-red spectrum is compatible with this structure and becausereduction to the corresponding 17a-20-di0l followed by oxidation of theglycol with periodic acid yields an 0:,[3- unsaturated ketone which isbelieved to be a 16-methylene 17-ketone.

Enforced acylation of the 3,6-acyloxy-17a-hydroxy-6-methyl-16-methylenepregn-5-en-20-one proceeds to give 3,8,17adiacyloxy-6-methyl-16-methylenepregn-5-en-20- one (V; where R and R' areacyl groups containing up to 6 carbon atoms) Me V Preferentialhydrolysis of the 3,8-acyloxy group gives the corresponding Pap-hydroxyacyloxy derivative having the general Formula V Where R is hydrogen andR is as hereinabove defined. Oxidation of the latter compound to :herequired 3-oxo-4,6-diene (I) is performed with a benzoquinone in thepresence of an Oppenauer oxidant.

Conversion of the 3,8-hydroxy or3fi-acyloxy-6sl6-dinethylpregna-S,16-dien-20-one (II) into the16a,17o-epox- .de (111; R=H) may be effected by means of tert.-butyliydroperoxide in alkaline solution or preferably with iydrogen peroxidein an alcoholic solution made alkaline with a hydroxide such as sodiumor potassium hydroxide. The reaction proceeds readily at 0 C. but may beaccel- :rated by using temperatures up to the boiling-point of lhealcohol used as solvent. Complete saponification of .he 3,6-acyloxygroup (if present) occurs during this re lCtlOIl and the product isacylated to give 3fl-acyloxy-16a,17a-epoxy-6-methyl-16-methylpregn-5-en-20-one (III; i=acyl). The3-acyl derivative of the 16a,17a-epoxide IIII; R'=acyl) is then treatedwith a source of hydrogen ons such as H 50 or HBr in a non-polar solventsuch as :or example, dioxan, benzene or ether at temperatures )elow 20C. and preferably in the range from 0 C. to LO C. when fission of theepoxide ring occurs with con- :omitant dehydration to yield the3,8-acyloxy-17a-hylroxy-6-methyl-16-methylenepregn-5-en 20 one (IV;acyl). Acylation of the last compound is efiected by :mploying enforcedconditions of acylation such as, for :xample, reaction with aceticanhydride in the presence at an acid catalyst such astoluene-p-sulphonic acid monolydrate at room temperature for 24 hours,giving 35,1704- liacy1oxy-6-methyl-16-methylenepregn-5-en-20 one (V;=R'=acyl).

Partial hydrolysis of the diacyl derivative performed by employing hotethanolic or methanolic lydrochloric acid, when the corresponding17a-acyloxy- 4 3fi-hydroxy-compound (V; R=acyl, R"=H) is obtained.

In converting the 3p-hydroxy A intermediate (V; R=acyl, R'=H) into therequired 3-oxo-4,6-diene (I) which is the subject of the presentinvention, (I; R=acyl) a quinone is employed, preferably p-benzoquinoneor chloranil (tetrachloro-p-benzoquinone); 2,3 dicyano-p- 'benzoquinoneor 2,3-dichloro-5,-6-dicyano-p-benzoquinone may also be employed. TheOppenauer oxidant is an aluminum alkoxide, preferably aluminumtert.-butoxide, aluminum iso-propoxide or an aluminum chlor-o-alkoxidesuch as aluminum chloro-iso-propoxide in a solvent which is preferablybenzene or toluene.

The solvent may be any convenient solvent or mixture of solvents inwhich the reactants are soluble and stable, such as benzene, toluene, orxylene, or mixtures of these with each other or with diluents such asdioxan, diethyl ether or tetrahydrofuran. The reaction is mostconveniently carried out by mixing the steroid and the quinone in one ofthe above mentioned solvents with a solution of the aluminum alkoxide inbenzene, toluene or xylene, but possible variations of this procedurewill be apparent to those skilled in the art. The reaction may becarried out at temperatures between 0 C. and the boiling point of thereaction mixture, the time required being reduced by employing highertemperatures. The preferred temperature for optimum yield, is roomtemperature, when the reaction takes up to 72 hours. At the refluxtemperature of the mixture, the reaction is complete within /2 to 2hours.

The product may be isolated by pouring the reaction mixture into anaqueous solution of sodium or potassium hydroxide, extracting thesteroidal material with a solvent such as ether, benzene or chloroform,and washing and evaporating the organic solution.

Following is a description by way of example of a method for carryingthe invention into effect.

EXAMPLE 1 3 3-acet0xy-6J 6-dimethyl-1 611,1 7mpovcypregn-5-em 20-0ne(III; R'=Ac) 3fi-acetoxy-6,l6-dimethylpregna-5,16-dien-20-one (6. 3 g.)dissolved in boiling ethanol (50 ml.) under reflux, was treated with 40%aqueous sodium hydroxide solution (3 ml.) followed by 30% hydrogenperoxide (8.5 ml.) and the mixture boiled for a further 30 minutes. Thereaction mixture was cooled and the crystalline product collected, driedand acetylated with acetic anhydride/ pyridine at C. for 1 hour andpurified from methanol to give 35acetoxy-6,16-dimethyl-16a,17a-epoxypregn 5 ene 20 one, needles, M.P. 118to 120 C. [a] 49 (c., 0.654 in chloroform).

3 fl-acetoxy-I 7 a-hydroxy-6-methyl-1 6-methylenepregn- 5-ert-20aone(IV; R'=Ac) 3B acetoxy 6,16 dimethyl 16or,17ot epoxypregn- 5-en-20-one(8 g.) dissolved in dioxan (200 ml.) cooled in an ice/ water bath wastreated with a 50% solution of hydrogen bromide in acetic acid (4 ml.)for 15 minutes. The dioxan was diluted with water and the productisolated With ether. The residue, after evaporation of the ether, wascrystallised from hexene to give 3fl-acetoxy- 17cc hydroxy 6 methyl 16-methylenepregn 5 en- 20-one, needles, M.P. about 126 to 128 C. or 147 to149 C., [a] -161 (c., 0.306 in chloroform).

3,8,17a-diacet0vcy-6-melhyl-1 6 -methylenepregn- 5-en-20-0ne (V; R=R'=A3,8 acetoxy 17oz hydroxy 6 methyl 16 methylenepregn-S-en-ZO-one (1 g.)and 'toluene-p-sulphonic acid monohydrate (150 mg.) were suspended inacetic anhydride (35 ml.) and left overnight at room temperature. Theclear solution was poured into water, and the product isolated withether. The residue from the ether extracts crystallised from hexane inplates to give the 3,8,17a-diacetoxy 6 methyl 16 methylenepregn 5 en 20-1 7 a-acetoxy-6-methyl-1 6-methylenepregna-4,6-diene- 3,20-dione (I;R=Ac) The above 3B-hydroxy-A -6-methyl compound (V; R=Ac, R=I-I) (2 g.)aluminium tert.-butoxide (2 g.) and p-benzoquinone (3.3 g.) weredissolved in dry benzene (200 ml.) and left at room temperature for 72hours. The benzene was washed with 5% aqueous sodium hydroxide solutionand with water, dried over sodium sulphate and evaporated under reducedpressure. The residue was crystallised from acetone/hexane to give therequired 17a acetoxy 6 methyl l6 methylenepregna- 4,6-diene-3,20-dione(I; R=Ac), needles, M.P. about 224 to 226 C., [a] -127 (c., 0.31 inchloroform) 222. 237.5 my (log 6 41.35)

EXAMPLE 2 3B-acetoxy-1 7a-caproyloxy-6-methyl-1 6-methy lenepregn-5-en-20-0ne (V; R=CO.C H R==Ac- 3,6 acetoxy 17a hydroxy 6 methyl 16methylenepregn-5-en-20 one (IV; R=Ac) (1 g.) and toluenep-sulphonic acidmonohydrate (150 mg.) were suspended in caproic anhydride (30 ml.) andthe mixture left at room temperature for 4 days. Pyridine (10 ml.) wasthen added and the mixture steam-distilled until no more organic matterwas present in the distillate, when the product was extracted from theresidual liquor with ether, and was obtained as a gum after removal ofthe ether.

1 7a-caproyloxy-3 ,B-hydrl0xy-6-methyl-1 6-methylenepregn- I 5-en-20-one(V; R=CO.C H R'=H) The foregoing product was heated under reflux inmethanol (100 ml.) containing concentrated hydrochloric acid (1 ml.) for1 hour, poured into water, and the product isolated with ether.

1 7u-capr0yl0xy-6-methyl-16-methylenepregna-4,6-diene- 3,2-0-di0ne (I;R=CO.C H

The foregoing product with aluminum tert.-butoxide (1 g.) andp-benzoquinone (1.6 g.) was dissolved in dry benzene (100 ml.) and themixture stirred at room temperature for 3 days. The benzene was washedwith 5% aqueous sodium hydroxide solution. The residue, after removal ofthe benzene, was a gum, which after chromatography on an alumina columnafiorded 17 a-caproyloxy-6-methyl-16-methylenepregna-4,6-diene-3,20-dione as a solid max.

We claim:

1. A process for the preparation ofl7a-acyloxy-6-methyl-l6-methylenepregna-4,6-diene-3,20-diones having thegeneral formula O OMe "OR i Toni Me (where R is an acyl group of ahydrocarbon carboxylic acid containing up to 6 carbon atoms) whichprocess comprises oxidising a 3fi-hydroxy or3,B-acyloxy-6,16-dimethylpregna-S,16-dien-20 one having the general for-5 mula (where R is hydrogen or an acyl group of a hydrocarbon carboxylicacid containing up to 6 carbon atoms) to the corresponding16a,l7o-epoxide having the general formula (where R is hydrogen or anacyl group containing up to 6 carbon atoms), acylating the16a,17u-epoxide in cases where R'-=H, converting the 16u,17a-epoxideinto a 17mhydroxy-16-methylene derivative having the general formula OOMe (where R is an acyl group of a hydrocarbon carboxylic acidcontaining up to 6 carbon atoms) by treatment with a source of hydrogenions, subjecting the l7a-hydroxy- 16-methylene derivative to enforcedacylation to give a diacyl derivative having the formula Me (V) (where Rand R are both acyl groups of a hydrocarbon carboxylic acid containingup to 6 carbon atoms), preferentially hydrolysing the diacyl derivativeto give the corresponding 3p-hydroxy-l7a-acyloxy derivative having thegeneral Formula V (where R is hydrogen and R is an acyl group of ahydrocarbon carboxylic acid containing up to 6 carbon atoms) andsubjecting the 3/3-hydroxy-l7aacyloxy derivative to an Oppenaueroxidation in the presence of a quinone.

2. A process as claimed in claim 1 wherein the 3/3-hy- :lroxy or3fl-acyloxy-6,16-dimethylpregna-5,16-dien-20- one is oxidised withhydrogen peroxide in alkaline alcoiolic solution.

3. A process as claimed in claim 1 wherein the source )f hydrogen ionsis sulphuric acid or hydrogen bromide 11 a non-polar solvent.

4. A process as claimed in claim 1 wherein the enforced rcylation iseffected by reaction with acetic anhydride in the presence oftoluene-p-sulphonic acid monohydrate.

5. A process as claimed in claim 1 wherein the prefer- :ntial hydrolysisis performed with hot ethanolic or methrnolic hydrochloric acid.

6. A process as claimed in claim 1 wherein the 33-hylroxy-17a-acyloxyderivative is mixed with a quinone 1nd reacted with a solution of analuminium alkoxide in I. solvent.

7. A process as claimed in claim 6 wherein the quinone s p-benzoquinoneor chloranil.

8. A process as claimed in claim 6 wherein the alun'inium alkoxide isaluminium tert.-butoxide in benzene.

9. 3B acetoxy 6,16 dimethyl 16u,17a epoxypregni-en-20-0ne.

10. 3 3 acetoxy 17oz hydroxy 6 methyl 16 methlenepregn-S-en-ZO-one.

11. 3,8,l7a diacetoxy 6 methyl 16 methylenetregn-5-en-20-one.

12. 17a acetoxy 3B hydroxy 6 methyl 16 meth lenepregn-S-en-ZO-one.

13. Compounds having the formula wherein R is selected from the classconsisting of hydrogen and an acyl group of a hydrocarbon carboxylicacid having up to 6 carbon atoms.

References Cited UNITED STATES PATENTS 1/ 1963 Mannhardt et al. 260397.4

OTHER REFERENCES ELBERT L. ROBERTS, Primary Examiner.

1. A PROCESS FOR THE PREPARATION OF 17 X-ACYLOXY-6-METHYL-1L-METHYLENEPREGNA-4,6-DIENE-3,20-DIONES HAVING THE GENERAL FORMULA 